scholarly journals Hepatic Bile Acid Reuptake in the Rat Depends on Bile Acid Conjugation but Not on Agonistic Properties towards FXR and TGR5

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2371
Author(s):  
Samuel A. J. Trammell ◽  
Jens S. Svenningsen ◽  
Jens J. Holst ◽  
Matthew P. Gillum ◽  
Rune E. Kuhre
Keyword(s):  
Bile Acid ◽  
Portal Vein ◽  
Plasma Concentrations ◽  
Vena Cava ◽  
Farnesoid X Receptor ◽  
Hepatic Bile ◽  
Caval Vein ◽  
Inferior Caval Vein ◽  
G Protein Coupled ◽  
Vena Portae

Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are the two known bile acid (BA) sensitive receptors and are expressed in the intestine and liver as well as in extra-enterohepatic tissues. The physiological effects of extra-enterohepatic FXR/TRG5 remain unclear. Further, the extent BAs escape liver reabsorption and how they interact with extra-enterohepatic FXR/TGR5 is understudied. We investigated if hepatic BA reuptake differed between BAs agonistic for FXR and TGR5 compared to non-agonists in the rat. Blood was collected from the portal vein and inferior caval vein from anesthetized rats before and 5, 20, 30, and 40 min post stimulation with sulfated cholecystokinin-8. Plasma concentrations of 20 different BAs were assessed by liquid chromatography coupled to mass spectrometry. Total portal vein BA AUC was 3–4 times greater than in the vena cava inferior (2.7 ± 0.6 vs. 0.7 ± 0.2 mM x min, p < 0.01, n = 8) with total unconjugated BAs being 2–3-fold higher than total conjugated BAs (AUC 8–10 higher p < 0.05 for both). However, in both cases, absolute ratios varied greatly among different BAs. The average hepatic reuptake of BAs agonistic for FXR/TGR5 was similar to non-agonists. However, as the sum of non-agonist BAs in vena portae was 2–3-fold higher than the sum agonist (p < 0.05), the peripheral BA pool was composed mostly of non-agonist BAs. We conclude that hepatic BA reuptake varies substantially by type and does not favor FXR/TGR5 BAs agonists.

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

scholarly journals Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sachiho Miyata ◽  
Yuji Kawashima ◽  
Miku Sakai ◽  
Masaya Matsubayashi ◽  
Keisuke Motoki ◽  
...  
Keyword(s):  
Bile Acid ◽  
High Fat Diet ◽  
Farnesoid X Receptor ◽  
High Concentration ◽  
Vitro Assay ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
G Protein Coupled ◽  
Dual Agonist

AbstractAlthough several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

2014 ◽  
Vol 171 (2) ◽  
pp. R47-R65 ◽  
Author(s):  
David P Sonne ◽  
Morten Hansen ◽  
Filip K Knop
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Bile Acids ◽  
G Protein ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Bile Acid Sequestrants ◽  
G Protein Coupled

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

Identification of potential dual agonists of FXR and TGR5 using e-pharmacophore based virtual screening

2015 ◽  
Vol 11 (5) ◽  
pp. 1305-1318 ◽  
Author(s):  
Thangaraj Sindhu ◽  
Pappu Srinivasan
Keyword(s):  
Bile Acid ◽  
Virtual Screening ◽  
Drug Development ◽  
G Protein ◽  
Farnesoid X Receptor ◽  
G Protein Coupled Receptor ◽  
Treatment Of Diabetes ◽  
Bile Acid Receptors ◽  
G Protein Coupled

Farnesoid X receptor and Takeda G-protein-coupled receptor-5 are well known bile acid receptors and act as promising targets for the drug development and treatment of diabetes.

Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function

Hepatology ◽  
2010 ◽  
Vol 52 (4) ◽  
pp. 1341-1349 ◽  
Author(s):  
Alexandra Milona ◽  
Bryn M. Owen ◽  
Jeremy F. L. Cobbold ◽  
Ellen C. L. Willemsen ◽  
Isobel J. Cox ◽  
...  
Keyword(s):  
Bile Acid ◽  
Farnesoid X Receptor ◽  
Receptor Function ◽  
Hepatic Bile

scholarly journals Bile acid signaling in renal water regulation

2019 ◽  
Vol 317 (1) ◽  
pp. F73-F76
Author(s):  
Suchun Li ◽  
Chunling Li ◽  
Weidong Wang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Renal Physiology ◽  
Urinary Concentration ◽  
Special Focus ◽  
Aquaporin 2 ◽  
Water Handling ◽  
Bile Acid Receptor ◽  
G Protein Coupled

Emerging evidence has shown that bile acids play important roles in renal physiology and diseases by activating two major receptors, the nuclear farnesoid X receptor (FXR) and the membrane G protein-coupled bile acid receptor-1 (Gpbar1; also known as TGR5). Both FXR and TGR5 have been identified in human and rodent kidneys, where they are deeply involved in renal water handling. In mice, FXR- or TGR5-related gene deficiency has been associated with reduced aquaporin-2 expression accompanied with impaired urinary concentration ability. In this mini-review, we briefly discuss the current understanding of FXR/TGR5 signaling in the kidneys, with a special focus on the regulation of aquaporin-2 expression by bile acids in the collecting ducts and its potential significance in disease conditions.

Bile acid treatment and FXR agonism lower postprandial lipemia in mice

2020 ◽  
Vol 318 (4) ◽  
pp. G682-G693 ◽  
Author(s):  
Sarah Farr ◽  
Bogdan Stankovic ◽  
Simon Hoffman ◽  
Hassan Masoudpoor ◽  
Chris Baker ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Postprandial Lipemia ◽  
Dietary Lipid ◽  
Farnesoid X Receptor ◽  
Postprandial Lipid Metabolism ◽  
Glucagon Like Peptide 1 ◽  
Postprandial Lipid ◽  
Bile Acid Receptors ◽  
G Protein Coupled

Postprandial dyslipidemia is a common feature of insulin-resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. Although bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here, we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions, and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA (but not DCA) effects were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the antidiabetic hormone glucagon-like peptide-1 (GLP-1). Although the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate-limiting enzyme for bile acid synthesis. Bile acid signaling may be an important mechanism of controlling dietary lipid absorption, and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia. NEW & NOTEWORTHY We present new data suggesting potentially important roles for bile acids in regulation of postprandial lipid metabolism. Specific bile acid species, particularly secondary bile acids, were found to markedly inhibit absorption of dietary lipid and reduce postprandial triglyceride excursion. These effects appear to be mediated via bile acid receptors, farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Importantly, bile acid signaling may trigger glucagon-like peptide-1 (GLP-1) secretion, which may in turn mediate the marked inhibitory effects on dietary fat absorption.

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